Search PubMed⌕ Search

Biomedical subjects

B Arnold

Publications and source records attributed to B Arnold.

At least 73 records · Page 4Linked to original sources
PubMed1993

Multiple levels of peripheral tolerance.

The establishment and maintenance of self tolerance is based on multiple events in the thymus and periphery, resulting in either deletion of self-reactive T cells or induction of nonresponsiveness. Here, Bernd Arnold and colleagues propose that, depending on the tolerogenic signals, peripheral T cells can reach different levels of tolerance with regard to their capacity for reactivation. In addition, it appears that tolerant T cells are still susceptible to further tolerogenic signals, driving them into a deeper state of tolerance. Thus, induction of T-cell tolerance can be viewed as a multistep mechanism.

Animals↗
PubMed1993

[Ambulatory epidural morphine analgesia via a transcutaneous implanted spinal catheter].

This report deals with a patient suffering from recurring rectum carcinoma infiltrating the lumbosacral plexus who received ambulant treatment with spinal opiate supply by a pump device, using a transcutaneous spinal catheter over a period of 12 weeks. The catheter turned out to be simple to implant. During the whole period no malfunctions occurred. This form of spinal analgesic treatment allowed the patient a relatively pain-free life outside the hospital.

Ambulatory Care↗
PubMed1993

[Cartilage-specific autoimmunity in otosclerosis].

The otic capsule of patients with otosclerosis contains premature bone with numerous cartilaginous remnants. Some investigators have proposed that the pathogenesis of otosclerosis is related to these cartilaginous rests in the otic capsule. In this study we investigated the presence of a humoral immune reaction against cartilage-specific antigens using ELISA-methods in patients with otosclerosis. Concomitantly, 8 age- and sex-matched healthy blood donors, free of any symptoms of autoimmune disease, served as controls. The following antigen substrates were used: collagen (I, II, III, VI, IX and XI), chondrocytes and chondrocyte membranes. Findings then showed that the levels of antibodies to collagens type II and IX as well as to chondrocytes were higher in the otosclerosis patients than in the control subjects. The high titer of antibodies against chondrocytes was not accompanied by an increase in antibodies against the chondrocyte membranes. To our knowledge these observations represent the first evidence for the existence of autoantibodies against minor collagens and chondrocyte-specific antigens and support a possible role for a cartilage-specific autoimmunity in the etiopathogenesis of otosclerosis.

Adult↗
PubMed1992

Autoimmune diabetes as a consequence of locally produced interleukin-2.

During cell differentiation in the thymus, self-reactive T cells can be generated. The majority of these seem to be deleted after intrathymic encounter with the relevant autoantigen. As all self antigens are unlikely to be present in the thymus, some autoreactive T cells may escape censorship. Here we study the fate of these cells using transgenic mice expressing the class I molecule H-2Kb (Kb) in the insulin-producing beta-cells of the pancreas. These mice were crossed with mice transgenic for genes encoding a Kb-specific T-cell antigen receptor (TCR) which could be detected using a clonotype-specific monoclonal antibody. Although T cells expressing the highest level of transgenic TCR were deleted intrathymically in double-transgenic mice, Kb-specific T cells were detected in the periphery. These cells caused the rejection of Kb-expressing skin grafts, but ignored islet Kb antigens even after priming. But when double-transgenic mice were crossed with transgenic mice expressing the lymphokine interleukin-2 in the pancreatic beta-cells, there was a rapid onset of diabetes. These results indicate that autoreactive T cells that ignore self antigens may cause autoimmune diabetes when provided with exogenous 'help' in the form of interleukin-2.

Animals↗
PubMed1992

Anergy induced by thymic medullary epithelium.

Thymocytes can be rendered tolerant by non-deletional mechanisms upon interaction with major histocompatibility complex (MHC) antigens on thymic epithelium. Whether the epithelial cells in the cortex or medulla could mediate this effect was not clear so far. To address this question, a transgenic mouse was generated in which the bovine keratin IV promoter was used to control expression of the alloantigen Kb. In the periphery the Kb transgene was expressed on a subset of keratinocytes. In the thymus expression was restricted to a subpopulation of medullary epithelial cells. No expression was found in the cortex. Such a tissue distribution has been reported for the keratin IV molecule demonstrating the faithfulness of the promoter used here. To follow the fate of the Kb-reactive thymocytes, this mouse was mated with another transgenic mouse expressing an anti-Kb T cell receptor (TcR). In the double-transgenic mice the CD8+CD4- thymocytes were not deleted but they were found to be anergic as assayed by their failure to be activated in vitro by either Kb-positive spleen cells or by cross-linked anti-TcR antibodies. These observations establish that expression of an MHC class I antigen in the thymic medullary epithelium is sufficient to induce anergy in the mature CD8+CD4- thymocyte population.

Animals↗
PubMed1992

Expression of major histocompatibility complex class I antigens at low levels in the thymus induces T cell tolerance via a non-deletional mechanism.

Transgenic CBA (H-2k haplotype) mice expressing the H-2 Kb major histocompatibility complex (MHC) class I gene under control of transcriptional promoter elements from a milk protein gene display high-level H-2 Kb transcription in lactating mammary glands and low-level transcription in skin and thymus of male and virgin female transgenic mice. However, H-2 Kb antigen could be detected only in lactating mammary gland epithelial cells by immunohistological methods. All transgenic mice are tolerant of H-2 Kb since they fail to reject skin grafts from mice expressing H-2 Kb molecules. Furthermore, anti-H-2 Kb cytotoxic responses could not be generated using responder T cells from transgenic mice but T cells from the same mice proliferated, in the presence of interleukin-2, in response to stimulator cells expressing H-2 Kb. Tolerance to H-2 Kb is induced in the thymus since CBA mice grafted with thymus tissue from transgenic mice fail to reject H-2 Kb disparate skin grafts. However, experiments with double-transgenic mice also expressing a T cell receptor with anti-H-2 Kb specificity reveal that tolerance induction is not brought about by elimination of thymocytes bearing H-2 Kb-reactive receptors. Instead, a non-deletional mechanism which results in down-modulation of both CD8 and T cell receptor expression in peripheral T cells correlates with the induction of tolerance in these mice. These data reveal that extremely low levels of self-antigen expression in the thymus are sufficient to induce tolerance via non-deletional mechanisms.

Animals↗
PubMed1992

Serial studies of autologous antibody reactivity to squamous cell carcinoma of the head and neck.

In previous studies we evaluated the incidence and specificity of autologous antibody reactivity against squamous cell carcinoma of the head and neck (SCCHN). We were able to demonstrate that autologous antibody reactivity is present in native sera but was usually of too low a titer to allow further analysis. Dissociation of immune complexes by acidification and ultrafiltration of serum augmented autologous antibody reactivity in nine out of nine autologous systems tested. Native antibody and antibody derived from immune complexes produced by the host and reactive with autologous tumor cells may be directed against physiologically relevant antigens. Therefore, correlations of antibody titers with clinical course may provide insight into the nature of the host response to cancer. In the present analysis, serological studies of six patients with SCCHN were performed with serum samples obtained over many months. Results of serial serological assays were correlated to tumor progression and clinical course. Fluctuations in autologous antibody reactivity were noted over time. In four cases, rises in autologous antibody titers preceded the clinical diagnosis of recurrence by several months. Drops in autologous antibody reactivity were noted in two cases following surgery or radiation therapy. In two cases of long-term survivors, no correlation between antibody reactivity and clinical course was noted. Specificity analysis of the six autologous systems demonstrated reactivity against autologous and allogeneic SCCHN as well as melanoma cell lines. These sera did not react with glioma, neuroblastoma, renal cell, breast, bladder and colon carcinoma cell lines nor with fetal calf serum, pooled lymphocytes, red blood cells and platelets. Autologous serial serological studies may provide a means by which to evaluate the host/tumor relationship in patients with SCCHN.

Aged↗
PubMed1992

Extrathymic T-cell selection.

The T-cell repertoire is formed during T lymphocyte maturation in the thymus. There is, however, increasing evidence that there are additions to, and modifications of, this repertoire by extrathymic events. Most importantly, mature peripheral T cells are not only susceptible to activation signals but also to tolerance induction upon encounter of extrathymic antigen. An understanding of these inactivation processes should result in strategies for specific immunosuppression in organ transplantation and autoimmune diseases.

Animals↗
PubMed1992

T cell activation and thymic tolerance induction require different adhesion intensities of the CD8 co-receptor.

Activation of mature lymphocytes requires in addition to the TCR contact with the corresponding antigen the binding of the CD8 or CD4 co-receptors to MHC class I or class II proteins respectively. To investigate the contribution of the CD8-class I interaction to the elimination of autoreactive T cells during negative selection in the thymus we generated two types of transgenic mice. One set expressed a modified Kb molecule which contained a human HLA-A2 alpha 3 domain, thereby missing the binding residues for the murine CD8 molecules. The second set of mice expressed an anti-Kb specific TCR. Both lines were crossed and in the resulting double transgenic mice the development of Kb-reactive T cells was followed with an anti-clonotypic antibody. Surprisingly, efficient clonal deletion in the thymus was still observed, although the reduced CD8-class I adhesion abrogated effector functions in vivo and in vitro. These results imply that even T cells with intermediate affinity for self are negatively selected in the thymus despite the fact that they are not able to react against self antigens in the periphery. Thus a safety window is created which decreases the risk of autoaggression.

Animals↗
PubMed1992

Threshold tolerance in H-2Kb-specific TCR transgenic mice expressing mutant H-2Kb: conversion of helper-independent to helper-dependent CTL.

To evaluate the role of the structure of the class I molecule and associated peptide(s) in intrathymic selection and tolerance, mice expressing as a transgene (tg) a TCR specific for the H-2Kb alloantigen were crossed with mice expressing the mutant class I molecule H-2Kbm1 or H-2Kbm8. In H-2k/k TCR tg mice (in a situation of exclusive positive selection), peripheral tg TCR expressing (Ti+) CD8+ T cells showed high, suboptimal, and an absence of reactivity for H-2Kb, H-2Kbm1, and H-2Kbm8, respectively. In the peripheral lymphoid organs of TCR tg H-2k/k, H-2k/bm8, H-2k/bm1, and H-2k/b mice respectively, the tg TCR was expressed on T cells with decreasing intensity of surface CD8. Thymic subpopulations of TCR tg mice presented a pattern of negative selection with decreasing intensity from H-2k/b to H-2k/bm1 and H-2k/bm8. This suggests that a weak interaction between the TCR and H-2Kbm8 exists which partially results in negative, but not in positive, intrathymic selection. Results further indicate that expression of H-2Kbm8 does not induce tolerance to H-2Kb. In H-2k/bm1 mice, the peripheral Ti+ CD8lo cells express two distinct types of 'threshold' tolerance in vitro: (i) they generate cytotoxic T lymphocytes (CTL), in the presence of exogenous IL-2, which fail to respond to H-2Kbm1 but remain reactive to H-2Kb; and (ii) they do not make significant titers of IL-2 and do not significantly proliferate in response to H-2Kb, unlike the Ti+ CD8+ T cells from H-2k/k TCR tg mice which respond efficiently. These results show that tolerance is induced up to a level of non-reactivity within a given MHC environment: for the same TCR, CTL reactivity to H-2Kbm1 is totally lost, whereas CTL reactivity to H-2Kb is only slightly reduced. Additionally, proliferation and IL-2 production by Ti+ CD8+ cells in response to H-2Kb were strongly affected in H-2k/bm1 mice. Thus, in H-2k/k mice the Ti+ CD8+ cells behave as helper-independent, whereas in H-2k/bm1 mice CD8+ cells expressing the same TCR behave as helper-dependent CTL.

Animals↗
PubMed1992

Influence of antigen density on degree of clonal deletion in T cell receptor transgenic mice.

The extent of peripheral clonal deletion of the T cell antigen receptor (TCR) from a CD8-dependent cytotoxic T lymphocyte of H-2k origin with alloreactivity for H-2Kb was measured in a TCR transgenic (Tg) model by use of a clonotype-specific mAb (anti-Ti mAb). Deletion varied depending on whether the TCR Tg was expressed in mice heterozygous (H-2k x b) or homozygous (H-2b x b) for the H-2Kb antigen. CD8 surface staining and functional analyses of peripheral T cells stimulated with polyclonal activators in bulk culture or by limiting dilution confirmed that in the H-2b x b mice few Ti+ cells were generated as measured by anti-Ti mAb-dependent target cell killing; while such cells could readily be detected in the H-2k x b mice. The latter maintained non-responsiveness to H-2Kb, as measured by cytolysis of H-2Kb-expressing tumor target cells, due to their down-regulation of surface CD8 expression. The question of whether the difference between H-2b x b and H-2k x b mice was due to the influence of positive selection imposed by the k haplotype in the H-2k x b hybrid, or to the lower antigen density in heterozygous than homozygous mice was addressed by analysis of H-2b x d Tg mice, H-2d being a non-selecting haplotype. Results obtained were similar for H-2b x d and H-2k x b Tg mice, suggesting that the density of the H-2Kb antigen may be one of the parameters controlling the extent of clonal deletion in the thymus.

Animals↗
PubMed1992

Distinct mechanisms of extrathymic T cell tolerance due to differential expression of self antigen.

Self-reactive T lymphocytes escaping thymic tolerance induction can be rendered non-responsive by contact with antigens in the periphery. In order to determine the parameters controlling peripheral tolerance induction we followed the fate of one well-defined self-reactive T cell population in three different mice expressing the self antigen in various nonlymphoid tissues outside the thymus. This was achieved by crossing anti-Kb T cell receptor (TCR) transgenic mice with transgenic animals expressing the Kb antigen exclusively on hepatocytes or keratinocytes or neuroectodermal cells. Due to this differential expression clonotype+, anti-Kb reactive T cells were found to exist at three different levels of tolerance. These levels were distinct with regard to downregulation of TCR and CD8 molecules, and the requirements for reexpression of TCR in vitro. This differential induction of peripheral tolerance suggest that some tissues are more likely to be affected in autoimmune diseases than others.

Animals↗
PubMed1992

Modulation by interferon alpha and gamma of the expression of a melanoma-associated antigen detected by autologous antibody.

Interferons (IFN) are known to alter the expression of histocompatibility and tumour-associated antigens. We have reported the isolation and purification of a 66-kD melanoma-associated antigen (MAA) that is recognized by the host. Competitive binding with MAA reduced autologous antibody binding to five melanoma cell lines, suggesting that a similar antigen is detected by other patients with melanoma. Nine melanoma cell lines were incubated for 3 days with 0.01-100 units/ml of interferon alpha (IFN-alpha) or interferon gamma (IFN-gamma) and the maximum titre of autologous antibody reactivity was determined by protein A haemadsorption. Incubation with IFN-alpha or IFN-gamma resulted in a decrease in maximum titre of autologous antibody reactivity directed against all melanoma cell lines. A 3-day incubation of three melanoma cell lines with IFN-gamma augmented the expression of HLA-DR, as has been reported by others. Incubation with spent media from autologous melanoma cells exposed to IFN-alpha inhibited autologous antibody binding less than control media from melanoma cells to which no IFN was added, indicative of decreased production or internalization of MAA. Conversely, incubation with spent media obtained after exposure to IFN-gamma inhibited autologous antibody binding to a greater degree than control spent media, consistent with increased shedding of antigen. These results suggest that IFN-alpha and IFN-gamma down-regulate the expression of MAA detected by autologous antibody by different mechanisms of action.

Antigenic Modulation↗
PubMed1992

Recombinant human TNF-alpha stimulates the secretion of granulocyte colony-stimulating factor in vivo.

Tumor necrosis factor (TNF) is a macrophage-derived cytokine that causes hemorrhagic necrosis of several human tumors in vitro. It has a wide range of biologic effects including stimulation of secretion of both granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) by normal adult lung fibroblasts in culture. No in vivo data are available on the effect of exogenously administered TNF on cytokine production. In the studies reported here, we show that G-CSF accumulates in the serum in vivo in response to recombinant TNF (rTNF) administration. At the peak of the response circulating levels of 2-6 ng/ml of biologically active G-CSF are detectable. Surprisingly, circulating levels of GM-CSF, interleukin-3 as well as a number of other cytokines were not detectable within the limits of the assays. The results indicate that the levels of GM-CSF or interleukin-3 are minimally 100-fold lower than the peak levels of G-CSF. These data illustrate the complex interplay that cytokines have in vivo. Understanding these interactions in humans is crucial to the correct use of this new class of agents in the clinic.

Adenocarcinoma↗
PubMed1991

Uneven tissue distribution of minor histocompatibility proteins versus peptides is caused by MHC expression.

Naturally processed minor histocompatibility (H) peptides corresponding to H-4b, H-Y, and an unmapped BALB.B minor H gene were quantified in a relative way in 15 different tissues of male BALB.B mice. For one of these minor H antigens, we could also determine the relative content of the respective protein. For each minor H peptide, an individual tissue distribution was found. Tissues expressing little or no MHC (major histocompatibility complex), like brain, contained only small amounts of minor H peptides or none at all, although the same tissues contained minor H protein in substantial quantities. By contrast, Kb-expressing brains from mice transgenic for Kb under control of the glial acidic protein promoter contained both minor H peptide and protein in high amounts. Thus, the expression of minor H peptides in a given tissue is dependent on coexpression of the restricting MHC class I molecules.

Animals↗
PubMed1991

Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction.

By generating two types of transgenic mice we have investigated how extrathymic events can contribute to self tolerance. The major histocompatibility complex class I gene Kb was expressed under the control of the glial fibrillary acidic protein promoter in cells of neuroectodermal origin outside the thymus. These mice were tolerant to Kb. When crossed to transgenic mice expressing a Kb-specific T cell receptor (TCR), clonotype+, CD8+CD4- mature T cells could be detected in normal numbers in the thymus of the double-transgenic mice but were strongly reduced in spleen and lymph nodes in comparison with TCR single-transgenic mice. After isolation of clonotype negative splenic T cells and activation in vitro, reappearance of the clonotype+, CD8+CD4- cells was observed. These results indicate that down-regulation of TCR and CD8 molecules on the antigen-specific T cells is a novel mechanism, by which peripheral tolerance to this antigen can occur.

Animals↗